The pyrazole derivatives of the present invention are 3-aryl-5-alkoxy-pyrazoles represented by general formula (I): ##STR2## wherein Ar represents an aryl group, substituted as necessary; R represents a hydrogen atom or an alkyl, phenyl or benzyl group; R.sub.1 and R.sub.2, which may be the same or different, each represent a hydrogen atom or an alkyl group, or together form a 5 to 7 membered heterocyclic ring with the nitrogen atom to which they are attached; and n is an integer of from 1 to 4; and the pharmaceutically acceptable salts.
The invention also provides a process enabling the preparation of the derivatives of general formula (I) from easily accessible, known starting materials, providing a good yield.
The invention even further provides the use of the pyrazole derivatives of general formula (I) and their pharmaceutically acceptable salts, in human or veterinarian medicine, in particular for the treatment of cardiac arrhythmias.
The aryl group represented by Ar in general formula (I) can be, in particular, a phenyl group which may be substituted by one or more halogen atoms or alkyl, alkoxy, cyano, nitro or hydroxy groups. R can represent a hydrogen atom or a linear or branched alkyl group, such as methyl, ethyl, isopropyl, n-butyl, t-butyl, isoamyl, etc., or a phenyl or benzyl group.
When R.sub.1 and R.sub.2 form a heterocyclic ring with the nitrogen atom to which they are attached, this heterocyclic ring can be a group completed by carbon atoms, for example a pyrrolyl, pyrrolidinyl, piperidyl, azepinyl group, etc. This heterocyclic ring can also contain one or more other heteroatoms such as nitrogen and oxygen, and for example oxazolidinyl, pyrazolyl, piperazinyl, imidazolyl, morpholinyl, pyrazolinyl groups, etc., are representative.
In general formula (I) above, Ar preferably represents a phenyl group, or a phenyl group substituted with one or more halogen atoms such as chlorine, bromine or fluorine, and, for example, a p-chlorophenyl group or a 3,4-dichlorophenyl group. R preferably represents a hydrogen atom, a lower alkyl group with 1 to 4 carbon atoms, such as a methyl, ethyl or propyl group, or a benzyl group. R.sub.1 and R.sub.2 preferably represent a lower alkyl group with 1 to 4 atoms, such as a methyl or isopropyl group, R.sub.1 being a hydrogen atom whereas R.sub.2 is an alkyl group, or the contrary, or together form a heterocyclic group as described above and, more particularly, a pyrrolidinyl, piperidyl, oxazolidinyl, piperazinyl or morpholinyl group. n preferably is 2 or 3.
The 3-aryl-5-alkoxy-pyrazoles of the present invention exist in several forms represented by formula (I) above and formulae (IA) and (IB) below: ##STR3##
The (I) and (IA) forms are predominant, but external factors may shift the equilibrium towards the (IB) form. The invention, of course, relates to the 3-aryl-5-alkoxy-pyrazoles in all the forms (I), (IA) and (IB) shown above.
The invention also provides salts of the pyrazole derivatives represented by general formula (I) above, and in particular, the pharmaceutically acceptable salts obtained by reacting a conventional mineral or organic acid, such as hydrochloric, sulfuric, lactic, oxalic, citric, phosphoric, stearic, maleic or tartaric acid, etc., with the derivative. The reaction can be carried out using conventional techniques, the acid and the derivative generally reacting in substantially stoichiometric proportions.
The pyrazole derivatives in accordance with the invention, shown by general formula (I), can be prepared from pyrazolones of formula (II): ##STR4## wherein Ar and R have the same meaning as in formula (I), by alkylation in a basic medium with a haloalkylamine of general formula (III): EQU X--(CH.sub.2).sub.n --NR.sub.1 R.sub.2 (III)
wherein X represents a halogen atom such as chlorine or bromine, and n, R.sub.1 and R.sub.2 have the definitions indicated in general formula (I).
The 3-aryl pyrazolones of formula (II) used as starting materials are known compounds which can be prepared in accordance with conventional techniques, such as are described for example in The Chemistry of Heterocyclic Compounds, Weissberger, Ed., Intersciences Publ., (1964).
The alkylation reaction of the 3-aryl pyrazolones of formula (II) with the haloalkylamines of formula (III) can be carried out in a basic medium in the presence of a base such as a hydride, an amide, a carbonate or an alkaline metal alkoxide or an amine, in an appropriate organic solvent.
The reaction can, for example, be carried out in the presence of sodium hydride, sodium amide, potassium hydride, sodium ethylate, potassium carbonate, sodium carbonate, diethylamine, triethylamine, etc., in a solvent selected from among dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, an alcohol such as methanol or ethanol, and acetone. When the solvent is an alcohol, it may be preferable to use a corresponding alkoxide as a base, for example, sodium ethoxide in ethanol. In accordance with the invention, sodium hydride in dimethylformamide, potassium carbonate in dioxane or sodium ethoxide in ethanol are preferably used.
The reaction can take place at ambient temperature, but it may be preferable to heat the reaction mixture to a temperature of between 30.degree. and 100.degree. C., and preferably between 40.degree. and 70.degree. C., in order to accelerate the reaction.
In accordance with a preferred method for the process of the invention, the pyrazolone of formula (II) is dissolved in an organic solvent in a nitrogen atmosphere, a base such as sodium hydride, potassium carbonate or sodium amide is added, the mixture is then heated slightly and the haloalkylamine of formula (II) is added progressively. The solvent is removed by evaporation under reduced pressure and the product obtained is purified using conventional acido-basic or chromatographic extraction techniques.
The haloalkylamines of fomrula (III), which are used to carry out the alkylation of the pyrazolones of formula (II) in accordance with the process of the invention, are generally commercially available in their hydrochloride forms. At the time of use, it may be preferable to transform these hydrochlorides into corresponding bases, by dissolving them in a solution saturated with potassium carbonate and carrying out an extraction, in accordance with the technique described in Fieser and Fieser, Reagents for Organic Synthesis, No. IV, John Wiley & Sons (1974).
N-(2-chloroethyl)-dimethylamine, N-(3-chloropropyl)-dimethylamine or N-(2-chloroethyl)-diisopropylamine, or even heterocyclic haloalkylamines such as N-(2-chloroethyl)-pyrrolidine, N-(2-chloroethyl)-piperidine, N-(3-chloro-propyl)-morpholine, N-(3-chloropropyl)-piperidine, etc., may in particular be cited as examples of useful haloalkylamines which can be used in accordance with the invention.
In accordance with one embodiment of the present invention, the pyrazole derivatives of general formula (I) can be prepared from an ethyl aroylacetate of general formula (IV): ##STR5## wherein Ar and R have the same meaning as in formula (I), which is transformed by transesterification using an aminoalcohol of formula (V): EQU HO--(CH.sub.2).sub.n --NR.sub.1 R.sub.2 (V)
wherein n, R.sub.1 and R.sub.2 have the same meaning as in formula (I), in order to obtain a compound of formula (VI): ##STR6## on which cyclization is carried out using hydrazine in an acid medium, yielding the derivative of general formula (I).
The transesterification enabling the transformation of the ethyl aroylacetate of formula (IV) into the ketonic ester of formula (VI) is preferably carried out by heating in a solvent enabling azeotropic distillation. Moreover, it is preferable to conduct the reaction in the presence of an acid catalyst. The solvent can, for example, be a hydrocarbon such as toluene or xylene.
The cyclization reaction using hydrazine in an acid medium, for example, in concentrated hydrochloric acid or a sulfuric acid medium, can be carried out in accordance with a technique analogous to that of H. J. Backer and W. Meier, Rec. Trav. Chim. P. B. 45, 428 (1926).